Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation. Altogether, our data unravel a novel molecular mechanism and immune functions for TAM and 4HT, sustaining their repurposing in infective and other estrogen receptors-unrelated pathologies.

ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen / G. Pepe, C. Sfogliarini, L. Rizzello, G. Battaglia, C. Pinna, G. Rovati, P. Ciana, E. Brunialti, F. Mornata, A. Maggi, M. Locati, E. Vegeto. - In: BIOMÉDECINE & PHARMACOTHÉRAPIE. - ISSN 0753-3322. - 144(2021 Dec), pp. 112274.1-112274.11. [10.1016/j.biopha.2021.112274]

ERα-independent NRF2-mediated immunoregulatory activity of tamoxifen

G. Pepe
Primo
;
C. Sfogliarini
Secondo
;
L. Rizzello;C. Pinna;G. Rovati;P. Ciana;E. Brunialti;F. Mornata;A. Maggi;M. Locati;E. Vegeto
2021

Abstract

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ERα)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17β-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGFα and other immune activation genes by ERα- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNFα and IL1β, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1β secretion through caspase-1 activation. Altogether, our data unravel a novel molecular mechanism and immune functions for TAM and 4HT, sustaining their repurposing in infective and other estrogen receptors-unrelated pathologies.
tamoxifen; macrophage; inflammation; drug repurposing; Nrf2
Settore BIO/14 - Farmacologia
7PQCP-CSA12AMAGG_CEND_M - Imaging of Neuroinflammation in Neurodegenerative Diseases - MAGGI, ADRIANA CATERINA - 7PQCP-CSA - 7 Programma Quadro_Collaborative Project/Network/Coordination and Support Action - 2012
PRIN201719MLOCA_01 - Cell plasticity of tumor-associated immune infiltrate: molecular mechanisms and therapeutic options - LOCATI, MASSIMO - PRIN2017 - PRIN bando 2017 - 2019
H2020_ERC20AARNO_01 - Pandemics Outbreaks Rationalized: towards a universal therapy to eliminate intracellular pathogens and drug resistance (PANDORA) - RIZZELLO, LORIS - H2020_ERC - Horizon 2020_Europern Research Council - 2020
12-ott-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/877271
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